Abstract Alzheimer?s disease (AD) is the most common neurodegenerative disease among the elderly and is characterized by a global decline in cognition including memory loss and reduced reasoning power, followed by severe neurodegeneration and death. In addition to the cognitive problems, a common manifestation of AD is a major disruption in sleep-wake cycles, with patients exhibiting excessive daytime sleepiness or changes in sleep timing and reduced circadian amplitudes. Familial AD cases only account for ~1% of afflicted individual, while the rest result from sporadic mutations that are likely influenced by many environmental and genetic factors. In these sporadic cases, the cause of the neuronal cell death is not known but appears to be through various cellular insults that result in toxic aggregations of amyloid-? (A?) protein (amyloid plaques) and hyperphosphorylated tau (neurofibrillary tangles; NFT) and increased oxidative stress. Although the existing data make difficult to determine whether oxidative stress or protein aggregation is the initiating event, these two processes clearly impact each other, and a growing body of evidence implicates oxidative stress as being involved in at least the propagation of cellular injury that leads to neuropathology in AD. In this supplemental application, we will explore the role of the circadian protein Nocturnin in the pathogenesis of AD. Our data suggest that Nocturnin is an important modulator of oxidative stress, with higher levels exacerbating stress and lower levels providing protective effects. Genome-Wide Association Studies (GWAS) has identified a variant in Nocturnin as one of the rare protective variants for AD, suggesting that plays a role in excessive oxidative stress responses that contribute to pathogenesis and we will examine this link through mechanistic work in both cells and mice in this proposal. There are currently no treatments that prevent neuronal cell loss in AD and we hypothesize that reduction of oxidative stress through the inhibition of Nocturnin might break the cycle of cell death.